UCLA

Despite significant improvements in cardiac care over the past 50 years, ischemic heart disease continues to be the leading cause of morbidity and mortality worldwide. While therapies such as percutaneous coronary intervention have greatly improved reperfusion rates in acute myocardial infarction, effective therapies for the prevention and treatment of ischemia-reperfusion injury remain lacking. Some of the causes for this may include certain technical limitations of drug therapy, such as poor bioavailability, which can potentially be addressed through use of nanoparticle-based targeted drug delivery. This thesis evaluates the use of a nanoparticle-based induced Cre system in the development of nanoparticles for ischemia targeting and drug delivery. PLGA/4-Hydroxytamoxifen nanoparticles were fabricated using an emulsion-solvent evaporation method. These nanoparticles were then demonstrated to successfully induce gene recombination in Rosa26-CreER x tdTomato and Rosa26-CreER x Rainbow transgenic mouse models both in vitro and in vivo, through direct intracellular delivery of 4-Hydroxytamoxifen to specific tissues. In addition, tissue specificity of gene recombination was enhanced through attachment of targeting antibodies such as CD31 and CD11b to the nanoparticles. Using this system, the uptake and drug delivery of nanoparticles to cardiac tissue subjected to ischemia-reperfusion injury was studied. Nanoparticle uptake and resultant drug delivery was found to be increased in areas of injury, and this uptake could be further increased by nanoparticle targeting of macrophages in the injury region. Control of vascular permeability through the administration of histamine was also found to influence nanoparticle uptake in certain organs. This research provides a framework for further studies to develop a nanoparticle-based system for delivery of targeted therapeutics for ischemia-reperfusion injury.